Abstract

Background

25-hydroxycholesterol (25-HC) is one of the oxysterols, which are oxidized derivatives
of cholesterol, and has been reported to be involved in the pathogenesis of atherosclerosis
and Alzheimer’s disease. In lung, the possible involvement of 25-HC in airway diseases
has been revealed. In the present study, we examined whether 25-HC affects the release
of cytokines and also modulates the responses of toll-like receptor 3 (TLR3) in airway
epithelial cells.

Methods

The effect of 25-HC on the release of cytokines from primary human bronchial epithelial
cells after stimulation with or without polyinosine-polycytidylic acid [poly(I:C)],
a ligand for TLR3, and the signal transduction were examined.

Results

25-HC significantly potentiated the release of interleukin-8 (IL-8) and IL-6 from
the cells. This effect was more potent compared with that of other oxysterols, 22-HC
and 27-HC. GW3965 and TO901317, synthetic agonists of liver X receptors that are receptors
for oxysterols, did not augment the IL-8 release. 25-HC enhanced the nuclear factor-kappa
B (NF-κB) DNA binding activity and translocation of phosphorylated c-Jun into the
nucleus. The release of IL-8 was inhibited by the NF-κB inhibitor, caffeic acid phenethyl
ester (CAPE), an inhibitor of nuclear factor kappa-B alpha (IκBα) inhibitor, BAY 11–7085,
and an inhibitor of nuclear factor kappa-B kinase-2 (IKK-2) inhibitor, SC-514, but
not by a c-Jun N-terminal kinase (JNK) inhibitory peptide, L-JNKi1. 25-HC significantly
potentiated IL-8 release in poly(I:C)-treated cells and the augmentation was inhibited
by CAPE, BAY 11–7085, and SC-514. Furthermore, 25-HC potentiated the translocation
of interferon regulatory factor 3 into the nucleus and the release of interferon-beta
(IFN-β) in poly(I:C)-treated cells.

Conclusions

These data demonstrated that 25-HC augments the release of IL-8 and IL-6 via NF-κB
signalling pathway and enhances the release of IL-8 and IFN-β after stimulation of
TLR3 in airway epithelial cells. 25-HC may be involved in the neutrophilic airway
inflammation through the stimulant effect of IL-8 and IL-6 release and also potentiate
the TLR3-mediated innate immunity in airway diseases.